Synaptic function of BK channel-interacting proteins

阿尔茨海默病（AD）是一种影响许多人的神经退行性疾病。大多数病例早发

Alzheimer’s disease (AD) is a neurodegenerative disorder inflicting many people. Most cases of early-onset familial AD are linked to mutations of presenilins. Previous studies on presenilins have focused on their roles in the generation of amyloid β (Aβ) because accumulation of Aβ plaques in brain tissue is generally considered the primary cause of AD. However, the amyloid hypothesis is being questioned because all anti-amyloid clinical trials have failed. Therefore, it is necessary to explore other potential mechanisms of presenilin function in AD. Among the known effects of presenilin mutations are reduced neurotransmitter release and calcium dyshomeostasis, which are both putative underlying mechanisms of AD. It is known that mutations of presenilins cause reduced neurotransmitter release and calcium dyshomeostasis, which are associated with and potentially caused by decreased ryanodine receptor expression. However, it is unknown how presenilins regulate ryanodine receptors. This proposal is to test the hypothesis that presenilins regulate ryanodine receptor expression by acting through some other regulatory proteins. The nematode Caenorhabditis elegans is used as an animal model to identify the putative regulatory proteins because many cellular mechanisms in mammalian systems, including the roles of presenilins in synaptic and ryanodine receptor function, are conserved in worms. The specific aims of this proposal are: 1) identify candidates for the putative regulatory proteins of ryanodine receptor expression by mass spectrometry and RNA-seq, and 2) determine whether the identified proteins are required for presenilins’ roles in neurotransmitter release and ryanodine receptor expression. Our long-term goal is to illustrate whether and how reduced neurotransmitter release and ryanodine receptor function play a role in the pathogenesis of AD caused by presenilin mutations.